Prevention of musculoskeletal diseases and other age-related complications, such as osteoporotic fractures, is dependent on developing proper bone mass at a young age in order to maintain the structural integrity throughout adulthood. Exercise provides a unique combination of dynamic loading and a systemic increase in PTH; two dominate forms of stimuli involved with bone formation. The research proposed in this fellowship application is focused on understanding the influence of PTH release during exercise on bone adaptation by the novel approach of manipulating the cellular response to PTH during exercise by inhibiting it with PTH(7-34) or increasing the cellular response with PTH(1-34). The central hypothesis states that PTH release during exercise enhances the tissue mechanics of bone and adaptation in the perilacunar matrix through osteocyte activity. To test this hypothesis, adolescent mice will be treated with PTH(7-34) or PTH(1-34) prior to moderate exercise to modify the cellular response to PTH during exercise. The first aim of this study will determine how PTH inhibition affects bone mineral content along with the tissue-level and structural-level properties of bone based on mechanical testing and histomorphometry analysis. The second aim of this study will identify the influence of exercise and the role of PTH release, on changes in tissue composition of cortical bone, specifically within the perilacunar matrix surrounding osteocytes, based on Raman spectroscopy analysis. In parallel, changes in gene expression among osteocytes will also be evaluated based on in-situ hybridization and qRT-PCR techniques. The use of PTH(7-34) to inhibit the cellular response to systemic changes in PTH during exercise will uncouple the influence of PTH on bone adaption from that incurred by dynamic loading. The clinical implications of this study extend to the importance of exercise during development to enhance bone quality and reduce the risk of future fracture among other musculoskeletal complications, such as osteoporosis. The goals of this study will be accomplished under the guidance of a team of mentors at the University of Michigan, who provide perspectives from biology, chemistry, and engineering. This interdisciplinary mentorship will contribute to the career development of the applicant to becoming an independent investigator under the F32 Kirschstein/NRSA award.